A major obstacle to defining cellular and molecular mechanisms of memory is the enormous complexity of synaptic regions specialized for memory. Although synaptic plasticity is the major focus of memory research, a simpler modification, long-term hyperexcitability (LTH), also appears important for memory, even though it has received far less experimental attention. The properties and mechanisms of newly discovered forms of LTH in highly accessible peripheral axons of sensory and motor neurons of the invertebrate, Aplysia, will be investigated. This LTH is characterized by key features associated with current memory models, including 1) long-lasting modifications induced by localized depolarization, 2} restriction of the modifications to intensely depolarized regions, and 3) dependence of the modifications upon local protein synthesis. The proposed studies will use behavioral, electrophysiological, and biochemical methods to investigate physiological and behavioral functions of axonal LTH (as well as short-term hyperexcitability, STH), mechanisms of induction of STH and LTH, mechanisms of expression of STH and LTH, and relationships of STH/LTH in axons to STH/LTH at other neuronal sites including presynaptic terminals and dendrites, and its role in short- and long-term sensitization of withdrawal behavior. Specific questions concern the contributions of STH/LTH to long-term synaptic facilitation, the roles (if any) of potential Ca2+ signals in inducing STH/LTH, the roles of other second messengers and protein kinases, the roles of serotonin, TGFbeta1, NO, and sensorin, and the identification of ionic conductances altered during STH/LTH. Mechanisms and functions of axonal LTH in diverse types of neurons in Aplysia may point to neglected or unrecognized plasticity mechanisms in the mammalian nervous system, and provide insight into fundamental mechanisms important both for normal memory and disorders of memory (such as occur following stroke), as well as for neuropathic pain and other clinical problems related to peripheral nerve injury.